CS197275B2 - Method of producing substituted 6-aryl-4h-s-triazolo-/3,4-c/thieno/2,3-e/1,4-diazepines - Google Patents

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE COVERED 197275 (11) (B2) Ě (22) Registered 14 07 76 (21) (PV 4674-76) (40) Published 31 07 79 (51) Int. Cl.3 C 07 D 493/14 OFFICE AND DISCOVERY OFFICE (45) Published 15 02 83 (72)

The inventor WEBER KARL-HEINZ dr., GAU-ALGESHEIM, BAUER ADOLF dr. and LANGBEIN ADOLF dr., INGELHEIM / RHEIN (NSR) (73)

Patent holder C.H. BOEHRINGER SOHN, INGELHEIM / RHEIN (NSR) (54) Method for producing substituted B-aryl-4H-s-triazolo- [3,4-c] thieno [2,3-e] -1,4-diazines 1

The present invention relates to a novel process for the preparation of substituted 6-aryl-4H-s-triazolo [3,4-c] thiophen-2,3-e] -1,4-diazepines of general formula VII

in which

R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 2 carbon atoms, R 2 represents a hydrogen atom, or R 1 together with R 2 is connected via an alkylene chain and together represent a five or six membered ring, R 3 represents a hydrogen atom, a straight-chain unbranched alkyl group having from 1 to 3 carbon atoms, an ω-hydroxyalkyl group having from 1 to 3 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, or a 5- or 6-membered saturated oxygen-containing ring; nitrogen, wherein the nitrogen ring is optionally substituted by a methyl group on the nitrogen atom and R 4 is a hydrogen, fluorine, chlorine or bromine atom, and acid addition salts thereof.

The preparation of the compounds of the general formula VII is carried out according to the following reaction scheme: 197275 197275 3 Η

1) r & dukce, -: -> 2) c, ykli, zac & (I) 4

(ID & D P ^ Sg Pencil) tnatkytoxonium- ftuorobophate non-bocJ PHs-ij

() (V) H, O 3) NH, 2; PB ^ 3

R3-C

N

g z .t g g AC g g g g

The conventional process for the preparation of thienotriazolodiazolides leads to the use of the same starting material, i.e. 2-haloacetyl amino-3-benzoyl-thiophene of formula I, via the corresponding amine, by cyclization to diazepinone, by activation of the carbonyl function and reaction with the derivative hydrazine to the final product. Although the synthesis steps are less than twelve in the process of the present invention, the process of the present invention yields almost twice the yield of total synthesis. It has been found that the formation of a triazole ring is a critical step in the synthesis of the final synthesis. product. This cyclization proceeds through the oxazepine molecule - probably spherical reasons - spontaneously and almost in a qualitative yield, while the corresponding reaction on the diazepine molecule requires longer duration, mostly with heating.

For the synthesis of thienotriazolodiazepine 197275

the ketone of general formula (I) is first reduced

wherein R 1 to R d are as defined above and X is halogen, amino or acyloxy, for example acetoxy or propionyloxy, to the corresponding carbinol of formula 1a

in which

R 1 to R d and X are as defined above,

the amino group is optionally converted to halogen, the acyl group is optionally removed, and the reaction product undergoes a cyclization reaction. Thienooxazines of formula II are obtained

in which

R 1 to R d are as defined above. The reduction of the ketone of formula I to the carbinol of formula Ia is carried out according to the invention by treatment with sodium borohydride in dimethylformamide or dimethylacetamide at a lower temperature, preferably between 0 and -10 ° C. Surprisingly, there is virtually no credit-cleavage of the X-residue or the hydrolytic cleavage of the -CO-CH2-X moiety, whereas in other solvents such as the lower alcohol, the cleaved re-actions of carbinol formation prevail.

The reduction of the compound of formula I in which X represents an amino group is expediently carried out using a starting material in which R1 is other than hydrogen; on the other hand, the nitro group is introduced into the subsequent reaction of the aminocarbinol with the halocarbinol treated with nitrous acid in a strongly acidic solution of hydrohalic acid.

When X is an acyloxy group, this group is cleaved after reduction by hydrobromide with strong alkali.

A loop through the functional aminoketone derivative has been shown to be necessary in the present case, as surprisingly it has been found that the 2-aminobenzoyl-thiophenes in question cannot be directly linked to the 2-aminobenzophenones which are readily reducible (cf. for example, DOS 1545 639) reduce to car-binols.

The carbamols of formula (Ia) obtained above are, unlike ketones of formula (I), sensitive to hydrolysis, particularly exceptionally alkali-stable, which is a condition for the high yields of the above-described hydrodoboronium reduction.

The cyclization of the carbinol of formula (Ia) on the oxaze-p5n of formula (II) following the reduction is carried out by treatment with a suitable alkali metal alkoxide or sodium hydride when X is halogen; preferably, sodium isopropoxide and sodium tert-butoxide are used for cyclization. As solvents, alcohols, tetrahydrofuran, dioxane, dimethylformamide or inert solvents such as benzene and its monologues can be used. The reaction temperature is dependent on the starting material used and is between 0 ° C and the boiling point of the solvent used. When X is hydroxy, cyclization is carried out with conventional water-dispersing agents such as thionyl chloride, sulfuric acid, polyphosphoric acid or dicyclohexylcarbodiimide

The introduction of the radicals R 1 and / or R 2 can be carried out in different reaction steps.

When R1 represents lower alkyl groups or together with R2 forms an alkylene chain, these are conveniently introduced into the thiophene ring.

In contrast, the halogen atom can be introduced as already in the acylaminoketone step of the formula or into the compound of formula II. Halogenation is carried out in both cases over a short period of time by reaction with an equivalent amount of halogen or a suitable halogenate, such as a sulfuryl halide or halosuccinimide or similar agents in solvents such as tetrachloromethane, chloroform, methylene chloride, dioxane, 197275 tetrahydrofuran, dimethylformamide or a suitable hydrocarbon, optionally with the addition of a tertiary organic base, for example pyridine. Depending on the starting material used and the method used, the halogenation reaction temperature is between room temperature and the boiling point of the reaction mixture. The starting materials of the formula I are known from the literature and can be obtained, for example, according to the method described in Mo-natsheften der Cherie, Vol. 104, p. 704 (1973).

The compounds of formula (II) are intermediates for the preparation of therapeutically substituted thieno [2,3-e] triazolo [3,4-c] -1,4-diazepines of formula (VII) as described, for example, in DAS 24 10030 in the patents. DE 2435041 and 2 445 430 and in DE 2 460 776 and in DOS 2 229 845.

These reaction products are obtained from the above intermediates by reaction with a carboxylic acid hydrazide, forming the corresponding thieno [2,3-e] triazolo [3,4-c] -4,1-oxazepine by opening oxazepine ring treatment with hydrogen halides, transferring the thus formed 4- (3-phenylhalomethyl) -2-thienyl-5-hydroxymethyl-1,2,4-triazoles to the corresponding 5-halomethyl-1-derivatives by cyclization with ammonia and dehydrogenation.

The thienotriazolodiazepines mentioned in the aforementioned patents have been shown to be anxiolytically effective in various pharmacological methods, and as an asvalve-relaxant, and in addition to intensive anticonvulsant activity. Furthermore, it has been found that these substances have the capacity to intensify intake of food in mammals. Notably, their extremely low toxicity.

The compounds of formula II obtained by the above process are subjected to the action of phosphorus pentoxide in a solvent such as dimethylformamide, diglyme or tetrahydrofuran, preferably with the addition of an alkali metal carbonate, pyridine or mixtures thereof. The temperatures used in this operation may vary between room temperature and the reflux temperature of the reaction mixture. In this process, the compounds of formula (III) (O) (III) are obtained (in which the radicals R < r > and R < 4 > have the abovementioned Y is mercapto, methoxy or methyl mercapto or halogen) wherein Y is mercapto.

These compounds are in tautomeric equilibrium with the corresponding thiono derivatives:

(lil *,)

These compounds can be reacted with alkylating agents, for example with methyl iodide, to give compounds of the general formula after conversion by treatment with a metalating agent such as sodium methoxide or sodium azide in a solvent to the corresponding salts. III wherein Y is methyl-mercapto.

Such compounds of formula (III) wherein Y is methoxy are obtained from compounds of formula (II) by reaction with methyl oxo-nium fluoroborate.

This compound is obtained by the method described by H. Meerwein et al., J. pr. Chem. (2), 147, 257 (1937) and 154, 83 (7939) of boron trifluoride-ether and epichlorohydrin are reacted in situ with the compound of formula II. Suitable solvents are, in particular, ethers or halogenated hydrocarbons, for example carbon tetrachloride. The reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

Compounds of formula III wherein Y is halogen are prepared by reacting a compound of formula II with an inorganic acid halide, preferably phosphorus pentachloride in an anhydrous organic solvent such as dioxane or tetrahydrofuran at temperatures between -50 and -j. -50 ° C. (The imidchloride obtained can be reacted in situ with the compounds of formula IV to give triazolothienooxazo-197275 10 pin of formula V. In special cases, however, the halogen derivative can also be isolated.)

The compounds of formula III are now reacted with a compound of formula IV

R 5 -CO-NH-NH 2 (IV) wherein R 3 represents a hydrogen atom, a straight-chain or branched alkyl group having 1 to 3 carbon atoms, a ω-hydroxyalkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 atoms carbon or a 5- or 8-membered, atomic, sulfur or nitrogen-containing nitrogen atom, wherein the nitrogen ring is optionally substituted by a methyl group on the nitrogen atom;

whereby a compound of formula V is obtained

in which

R1 to R-t are as defined above.

This reaction can be carried out at temperatures between 100 and 250 ° C, both without solvent and in solvents such as methanol, ethanol, dioxane, chloroform, tetrahydrofuran, benzene, toluene, xylene or in mixtures of these solvents, optionally in the presence of an acid catalyst (e.g. hydrochloric acid, sulfuric acid, acid phosphoric acid, polyphosphoric acid, acetic acid, propionic acid, benzene sulfonic acid or toluene-n-sulfonic acid); the intermediate of formula IIIc formed in the reaction

the radicals R 1 to R 1 are as defined above and are not isolated.

When thieno [2,3-e] triazolo [3,4-c] -1,1-oxazepine of the general formula V is used as the substance, the thienotriazolodlazepines of the general formula VI are obtained according to the following scheme:

IVb)

In this process, the oxazepine ring of the compound of formula V is first cleaved by treatment with a strong hydrochloric acid or bromodic acid at the oxygen atom. Generally, it is sufficient to leave the compound of formula V in a strong hydrochloric acid or hydrobromic solution for several minutes to several hours at room temperature. The hydrohalogen compound of formula (Va) formed in this reaction is extracted with a water-immiscible solvent, preferably with a chlorinated hydrocarbon such as chloroform or methylene chloride, in the cold of the reaction mixture and then added - suitably after evaporation of the reaction solution - phosphorus halide or a sulfur halide such as thionyl chloride or phosphorus tribromide. The reaction temperature is maintained between 0 ° C and 40 ° C, preferably at about 20 ° C.

After distilling off the excess halogen and optionally the solvent present, the residue consisting of the dihalogenide Vb is reacted with ammonia or ammonia-providing substances such as jeurotropin. Suitable solvents for the self-ammonia reaction are lower alcohols such as methanol or ethanol, ethyl acetate, dioxane, tetrahydrofuran or inert hydrocarbons such as benzene and homologues thereof; this reaction can also be used in liquid α-isak. The reaction temperature is between the boiling point of the solvent used, but is preferably carried out in an autoclave to give the compound of formula VI in an excellent yield. Instead of a compound of formula Va, it is also possible to react with a phosphorus halide or a sulfur halide with the corresponding dihydroxy derivative of formula Vc

These compounds are obtained by heating a strong acid solution of the compound of formula (V) and isolating them from the reaction solution by extraction in the same manner as the compound of formula (Va).

The dehydrogenation of the compounds of formula (VI) to the reaction products (VII) is carried out using suitable dehydrogenating agents such as, for example, halogens or compounds of higher oxidation levels of chromium or manganese, for example chromene, dichromate or permanganate. Examples of suitable solvents for halogenation include chlorinated hydrocarbons such as chloroform or methylene chloride. Suitably, the hydrohalic tertiary organic base formed, for example pyridine, is added to the coupling reaction.

The oxidation with said chromium or manganese compounds is carried out in a solvent such as acetone, tetrahydrofuran or dioxane.

Depending on the type of oxidizing agent, the reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

The reaction products of formula (VII) can be converted into their physiologically acceptable acid addition salts in a conventional manner. Acids suitable for the formation of salts are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulfamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, salicylic acid, methacetic or toluenesulfonic acid and the like.

The reaction products of formula (VII) as well as their acid addition salts have a pronounced anticonvulsant, anxiolytic and anti-aggressive effect over a dose range of 0.1 to 3 mg / kg with very low toxicity.

EXAMPLE 1 8-Bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1, 4-diazepine a, 1 mol = 314 g of 2-chloroacetylamino-3- (o-chlorobenzoylthiophene is dissolved in 500 billion dimethylformamide and, at 0 ° C, 36 g of sodium borohydride spray are added by intensive stirring over 1 hour). the reaction mixture is poured into 2 liters of water to form a greasy precipitate, the aqueous phase is decanted, the oily product is washed two to three times with water and extracted with methylene chloride, after drying the methylene chloride phase and evaporating, 300 g of an oil which slowly solidifies and the solidified product recrystallizes from 294 g (93.1% of theory) of 2-chloroacetylamino-3- [(o-chlorophenyl) hydroxymethyl] thiophene with a melting point of 118 DEG-120 DEG C. However, oil may also be used directly for the cyclization; 8 mol = 253 g 2-chloroacetylamino-3 - [(o-chloro) -2- Phenyl] hydroxymethyl thiophenol dissolved in 200 ml of isopropanol is added to a boiling solution of 52 g (2.25 mol) of sodium in 1.8 l of isopropane and the reaction mixture is refluxed for 5 minutes. Thereafter, the brownish suspension is poured into 1.5 liters of water and the solution is acidified with concentrated hydrochloric acid. The precipitated crystals were filtered off and washed with water. The wet residue was dissolved in 2 L of methylene chloride, the methylene chloride solution was dried over magnesium sulfate, the filtrates were evaporated and the residue was recrystallized from methanol. 246 g (87% of theory) of 5- (o-chlorophenyl) -thieno [2,3-e] -4,1-oxazepin-1-one are obtained, m.p. 175-176 ° C. b) 0.1 mol = 27.9 g of 5- (o-chlorophenyl) thieno- [2,3-e] -4,1-oxazepin-1-one was dissolved in 300 ml of chloroform and 8.5 ml of pyridine At room temperature, a solution of 5.5 ml of bromine in 50 ml of chloroform was added over 10 to 15 minutes. The solution decolorises immediately. The title compound precipitates, is filtered off and washed with ether. The yield of 7-bromo-5- (o-chlorophenyl) thieno [2,3-e] -4,1-oxazepinone was 30 g (83% of theory), m.p. 178-180 ° C (decomposition). c, a) 0.1 mol = 35.8 g of 7-bromo-5- (o-chlorophenyl) thieno [2,3-e] -4,1-oxazepinone is heated with 350 ml of diglyme, 24 g of phosphorus pentoxide and 19 g g of sodium bicarbonate at 60 ° C for 30 minutes. Then, the reaction mixture is poured into about 1 liter of ice water to form a crystalline precipitate which is filtered off, washed with water and dried. 37 g = 99% of theory of 7-bromo-5- (o-chlorophenyl) thieno [2,3-d] -4,1-oxazepine-2-thione with a melting point of 200 DEG C. (decomposition). n) 0.1 mol = 37.5 g of 7-bromo-5- (o-chlorophenyl) thieno [2,3-a] -4-oxazepine-2-thione is dissolved in 370 ml of tetrahydrofuran and added with 10 ml of hydrazine hydrate. After 5 minutes the reaction was stopped at room temperature. The solution is evaporated, the residue is taken up in methylene chloride, washed several times with water, the methylene chloride phase is dried and evaporated. The residue is taken up in 200 ml of ethanol and 50 ml of ortho-acetic acid triethyl ester are added. The reaction mixture was refluxed for 30 minutes, evaporated in vacuo and the residue crystallized in ether. The yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-thieno- [2,3-e] triazolo [3,4-c] -4,1-oxazepine is 34.5 g = 87% of theory. Melting point 146-148 ° C. d, of 0.1 mol = 39.6 g 8-bromo-6- (o-chlorophenyl) -1-methylthieno [2,3-b] triazolo [3,4-c] -4,1- 146 DEG-148 DEG C. is suspended in 250 ml of concentrated bromomethane. Once a clear solution is formed (after 15-20 minutes), this solution is diluted with 300 mL of ice water and extracted with ethylene chloride. The methylene chloride phase was dried and evaporated, and the residue was crystallized in ether. 52 g of 3-methyl-4- [3- (o-chlorophenylbromomethyl) -5-bromothien-2-yl] -5-hydroxymethyl-1,2,4-triazole hydrobromide (94% of theory) are obtained by heat melting 200aC (decomposition). (3) 0.05 mol = 27.9 g of hydrobromide is stirred with 100 ml of thionyl chloride for 30 minutes at room temperature. Thereafter, the excess thionyl chloride is distilled off in vacuo, the residue is taken up in methylene chloride and washed with ice water and dilute ammonia. The dried methylene chloride phase was evaporated and the residue triturated with ether. Yield: 24.2 g of 3-methyl-4- [3- (o-chlorophenylbromomethyl) -5-bromo-thienyl-2-yl] -5-chloromethyl-1,2,4-triazole, m.p. to 169 ° C. 7) 12.4 g of this compound is dissolved in 270 ml of methanol and 100 ml of liquid ammonia are added. The reaction mixture was then heated to 100 ° C in an autoclave for 30 minutes. The reaction mixture was evaporated, the residue was taken up in methylene chloride, washed with water, the methylene chloride phase was dried, evaporated and the residue was recrystallized from methanol. The yield of 8-bromo-6- (o-chlorophenyl-1-methyl-thieno- [2,3-e] triazolo [3,4-c] -5,6-dihydro-1,4-diazepine is 9 160 DEG-162 DEG C. e) 39.5 g = 0.1 mol 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s; Dissolve 162 ° C in triazole [3,4-c] thieno [2,3-a] -5,6-dihydro-1,4-diazepine in 500 ml of methylene chloride and 15 ml of pyridine and run to 10 ° C. 10 ml of bromine in 50 ml of methylene chloride are added with stirring at room temperature for minutes. The solution, which is immediately decolourised, is stirred for 30 minutes, then shaken several times with water, dried, evaporated and the residue recrystallized from ethanol. The yield of 8-bromo-6- (o-chlorophenyl) -1-methyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine is 36.9 g = 94% of theory m.p. 208-210 ° C.

Very good yields are also obtained when the dehydrogenation is carried out with potassium permanganate analogously to Example 3. Example 2 8-Bromo-6- (o-chlorophenyl) -1- [tetrahydropyran-4-yl] -4H-triazolo - [3,4-c] thieno [2,3-e] -1,4-diazepine 18 197278 0.01 mol = 3.74 g 7-bromo-5- (o-chlorophenyl) thieno [2,3 The e] -4, 1-oxazepine-2-thione obtained according to Example 1c, a) was boiled with 100 billion dioxane and 1.5 g tetrahydro-pyran-4-carboxylic acid hydrazine under reflux for 30 minutes. Thereafter, the reaction mixture is worked up as in Example 1c, (3). The yield of 8-bromo-6- (o-chlorophenyl) -1- [tetrahydropyran-4-yl] thieno [2,3-e] triazolo [3,4-c] -4,1-oxazepine is 2, 7 g (58% of theory, m.p. 182-184 ° C).

By an analogous procedure to that described in Example 1d) and 1e), 8-bromo-6- (o-chlorophenyl) -1- [tetrahydropyran-4-yl] thieno [2,3-e] triazolo [3 4-C] -5,6-dihydro-1,4-diazepine, m.p. 174-175 ° C, 98% of theory, mp 257-258 ° C. EXAMPLE 3 8-Bromo-6- (o-chlorophenyl) -1-cyclohexyl-4H-s-triazolo [3,4-c] thieno [2,3-e] -1,4-piazepine 4.65 g = 0.01 mol of 8-bromo-6- (o-chlorophenyl) -1-cyclohexyl-4H-s-triazolo [3,4-c] thieno- [2,3-e] -5,6-dihydro- 192 ° C, 1,4-diazepine, prepared from 7-bromo-5- (o-chlorophenyl) thieno [2,3-e] -4,1-oxazepine-2-thione (Example 1) 200 DEG C. through 8-bromo-6- (o-chlorophenyl) -1-cyclohexyl-thieno [2,3-e] triazolo [3,4-c] -4,1-oxazepine (analogously to Example 1c, (S), temperatures ranging from 172 to 174 ° C, as described in Example 1c, (S))

1B of Example 1 d, a) is dissolved in 100 ml of manganese and potassium distilled distillate. At the boiling point, 3 g of sodium dichromate in 15 ml of water are added first, followed by 2 ml of 20% sulfuric acid, and the mixture is allowed to boil for 30 minutes. The solvent was distilled off, the residue diluted with a small amount of water, basified with ammonia and extracted with methylene chloride. After washing, drying and evaporating the solvent, the crude product remains, which is recrystallized from ethanol. Yield 4.1 g = 88% of theory, mp 190-192 ° C. Instead of sodium dichromate, manganate potassium can also be used for dehydrogenation. In this case, the following procedure is followed: 4.65 g = 0.01 mol 8-bromo-6- (o-chlorophenyl) -1-cyclohexyl-4H-s-triazolo [3,4-c] thieno- [2,3 -e] -5,6-dihydro-1,4-diazepine is dissolved in a mixture of 50 ml of acetone and 50 ml of methylene chloride. 1.4 g of finely divided potassium permanganate was added in one portion and the mixture was stirred at room temperature for 6 hours. Manganese dioxide is eliminated. Filtration through Celite gave a pale yellow filtrate which was evaporated and the residue triturated with ether. 4 g = 86% of the title compound of melting point 190 DEG-192 DEG C. are obtained.

In an analogous manner to that described above, the following recombinant products were prepared via the above intermediates: 197275 R3 R4 Intermediate II Intermediate V Intermediate VI Reaction

melting point (° C) melting point (° C) melting point (° C) product VII melting point (° C) CH 3 Br 176 137-139 171-173 205-206 (decomposition)

WHAT IS ABOUT O CO O LO O O R H O L O L O L O O O O O O O 1 OJ RH OJ 1 OJ R I OJ I OJ | OJ 1 OJ OJ L 1 CO 4f l 1 CO 1 o 1 l OJ l CO l 1 05 o o o CD m rh • OJ OJ L OJ L OJ L OJ L OJ L OJ L OJ L OJ L OJ L OJ L OJ L OJ

co OJ OJ O OJ LT5 00 00 CO tx co 00 OJ OJ C 05 LT5 tx O CO Ό rH rH rH rH rH rH rH rl OJ H CO | I | 1 | 1 1 1 (1 1 3 rH o o 5 o 0 o o co lo in co o o r o CO 05 in s o cc Ph rH rH rH OJ rH r-1 rH rH rH OJ rH

CO rH O OO thi O OJ> s 05 JI 00 CO rH rH rH rH rH rH OJ 00 1 | O I 1 | I | 00 05 l «Η 1 o 05 i 1 05 CO 1 OJ 1 OJ 05 OJ co 00 CO CO rH rH rH rH rH rH rH

LO o O o O LO Ό LO CO CO 00 OJ rH CO r — MH OJ rH rH | | I | | I what in N Q 00 what 00 OJ what Os Os OJ rH rH OJ rH rH

O 00 rH 1 O CO rH O O O00 co COrH rH H 1 1 1 1 CO CO. t> rH rH h rl rH o o o u o u

-y

Í Pí Pí pa

ICK i — I-l o pa in ffi

O

W 'y p pa pa f-pa and f-f f-l pa pa pq

Claims (2)

197275 17 Example 4 8-Bromo-6- (o-chlorophenyl) -1-tetrahydrofuranyl- (3-4H-S-triazole 3,4-c] thieno [2,3-b] -1,4-diazepine 4,5 g (0.01 mol) 8-bromo-6- (o-chlorophenyl) -1-tetrahydrofuranyl- (3) -4H-s-triazolo [3,4-c] thieno [2,3-e] - Of 5,6-dihydro-1,4-diazepine, m.p. 163-165 ° C, dissolved in 50 mL of methylene chloride and 15 mL of 18 pyridine. To this solution, 10 ml of bromine in 50 ml of methylene chloride was added with stirring at room temperature over a period of 15 minutes and the solution was stirred for a further 30 minutes. The solution was then shaken with water, dried, the solvent was evaporated and the residue was recrystallized from ethanol. There were obtained 3.7 g (82.2% of theory) of the title compound, m.p. 190-191 ° C. The following compounds of formula (I) are prepared in an analogous manner: R1 R2 R3 R6 Melting point (° C) Br H Br H 2 C 5 H 5 H 2 O 2 Cl 210 Cl 223-225 Cl 1201-122 Subject Method for preparing substituted 6-aryl-4H -s-triazole [3,4-c] thieno [2,3-e] -1,4-diazepines of general formula VII wherein R 1 is hydrogen, halogen, C 1 -C 2 loweralkyl, R 2 is hydrogen or R 1 taken together by R 2 is connected via an alkylene chain and forms a 5 or 6 membered ring, R 3 is a hydrogen atom, a straight unbranched alkyl group with 1 to 3 carbon atoms, ω-hydroxyalkyl group having 1 to 3 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms or 5 or 6 membered saturated ring containing an oxygen atom, sulfur atom or nitrogen atom, the nitrogen ring being optionally nitrogen atom methyl substituted and Rd represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, and their acid addition salts, characterized in that the compound of formula I is reduced. wherein R 1 to R 4 are as defined above, and X is halogen, amino or acyloxy, by treatment with sodium borohydride in dimethylformamide or dimethylacetamide at temperatures between 0 and 10 ° C to give the corresponding carbinol formula Ia 19727S 19 wherein the radicals R @ 1 to R @ 4 and X are as defined above, the carbinol, optionally after conversion of the amino group to a halogen atom or removal of the acyl group, is reacted with cyclizing agents such as an alkali metal alkoxide, e.g. with sodium or tert-butoxide sodium or with sodium hydride when X = halogen, optionally with water-removing agents such as thionyl chloride, sulfuric acid, polyphosphoric acid, or dicyclohexylcarbodiimide; -ce II wherein the radicals R @ 1 to R @ 6 are as defined above, converted into a methoxy group by treatment with a phosphorus pentachloride mercapto group by treatment with a trimethyl oxonium fluoroborate, a halogenide of an inorganic acid, or a mixture of phosphorous pentasulfide, sodium amide and methyl iodide to form methyl mercapto, and of formula III wherein R 1, R 2 and R 4 are as defined above and Y is mercapto, methoxy or methyl mercapto, or halogen, is reacted with a compound of formula IV R 3 -CO-NH-NH 2 (IV) wherein R 5 is a hydrogen atom, a straight-chained unbranched alkyl group having 1 to 3 carbon atoms or an ω-hydroxyalkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a 5- or 6-membered saturated ring containing oxygen, sulfur or a nitrogen atom, wherein the nitrogen ring is optionally substituted by a methyl group on the nitrogen atom, whereby the compound of general formula V is obtained wherein R 1, R 2, R 3 and R 4 are as defined above, and the compound is then cleaved on the oxygen oxazepine ring atom by treatment with a strong hydrohalic acid, the obtained hydrohalide of formula Va. wherein R 1 to R 4 are as defined above, and H 1 is chlorine or atom, is extracted with a solvent which is not miscible with water, and halo is added to the residue. phosphorus or sulfur, the dihalogenivative of formula (Vb) formed wherein the radicals R 1 to R 4 are as defined above and Hal and Hal 2, which may be the same or different from each other, are chlorine or bromine, are reacted with ammonia or an ammonia-providing compound, whereupon the compound of formula VI thus obtained . 187275 22 21 (VI) wherein the radicals R 1 to R 4 are as defined above, dehydrogenated using halogen, compounds of higher oxidation levels of chromium or manganese, such as aluminum metal dichromate or alkali metal permanganate, and then optionally converted physiologically an acid addition salt. Severografia, n. P., Plant 7, Most